title: Loss of epithelial hypoxia-inducible factor prolyl hydroxylase 2 accelerates skin wound healing in mice.
abstract: Skin wound healing in mammals is a complex, multicellular process that depends on the precise supply of oxygen. Hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2) serves as a crucial oxygen sensor and may therefore play an important role during reepithelialization. Hence, this study was aimed at understanding the role of PHD2 in cutaneous wound healing using different lines of conditionally deficient mice specifically lacking PHD2 in inflammatory, vascular, or epidermal cells. Interestingly, PHD2 deficiency only in keratinocytes and not in myeloid or endothelial cells was found to lead to faster wound closure, which involved enhanced migration of the hyperproliferating epithelium. We demonstrate that this effect relies on the unique expression of β3-integrin in the keratinocytes around the tip of the migrating tongue in an HIF1α-dependent manner. Furthermore, we show enhanced proliferation of these cells in the stratum basale, which is directly related to their attenuated transforming growth factor β signaling. Thus, loss of the central oxygen sensor PHD2 in keratinocytes stimulates wound closure by prompting skin epithelial cells to migrate and proliferate. Inhibition of PHD2 could therefore offer novel therapeutic opportunities for the local treatment of cutaneous wounds.
authors.affiliation: Emmy Noether Research Group, University of Technology, Dresden, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kalucka
authors.forename: Andreas
authors.initials: A
authors.lastname: Ettinger
authors.forename: Kristin
authors.initials: K
authors.lastname: Franke
authors.forename: Soulafa
authors.initials: S
authors.lastname: Mamlouk
authors.forename: Rashim Pal
authors.initials: RP
authors.lastname: Singh
authors.forename: Katja
authors.initials: K
authors.lastname: Farhat
authors.forename: Antje
authors.initials: A
authors.lastname: Muschter
authors.forename: Susanne
authors.initials: S
authors.lastname: Olbrich
authors.forename: Georg
authors.initials: G
authors.lastname: Breier
authors.forename: Dörthe M
authors.initials: DM
authors.lastname: Katschinski
authors.forename: Wieland
authors.initials: W
authors.lastname: Huttner
authors.forename: Alexander
authors.initials: A
authors.lastname: Weidemann
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D039661:Integrin beta3 / Q000235:genetics; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D012879:Skin Physiological Phenomena; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039661:Integrin beta3; D016212:Transforming Growth Factor beta; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases